Multiple myeloma is a hematopoietic malignancy caused by terminally differentiated malignant plasma B-cells. Myeloma cells simultaneously activate the bone resorbing osteoclast cells in the bone marrow and inhibit bone forming osteoblast cells, culminating in a vicious cycle of tumor growth and bone destruction. A grim result of this interplay is that 80% of MM patients present bone lesions including pathologic fracture at diagnosis. Despite tremendous improvements in MM patient management, more than 24,000 new cases and 11,000 deaths occurred in 2014 alone. Despite the introduction of novel therapies, more than 90% of MM patients relapse, and nearly all patients will eventually die from MM. Therefore, a new strategy that increases treatment efficacy, prevents relapse, provides a cure and reduces off target toxicity is an urgent need. We propose to address this urgent medical need by (a) stimulating MM-specific therapy using sub-lethal doses of a chemotherapeutic to eliminate both chemo responsive and resistant MM cells and improve the quality of life; (b) utilizing nanoparticles to induce therapy in a sustainable and molecular pathway-independent method; and (c) incorporating both homing ligands, that will selectively deliver the nanoparticles to MM cells. An orthogonal MM targeting pathway will be used to co-localize an enabling light-emitting materials to facilitate a spatio-temporal treatment paradigm that spares healthy cells in the bone marrow. Imaging methods will be used to monitor response to treatment. We expect that the efficacy of treatment will be independent of the cancer cell phenotype. Because all components of the materials have been used in the clinic, we envisage seamless translation of the products to humans upon completion of this project.